Elizabeth G. Kelley

Stimuli-responsive copolymer solution and surface assemblies for biomedical applications

Stimuli-responsive polymeric materials is one of the fastest growing fields of the 21st century, with the annual number of papers published more than quadrupling in the last ten years. The responsiveness of polymer solution assemblies and surfaces to biological stimuli (e.g. pH, reduction-oxidation, enzymes, glucose) and externally applied triggers (e.g. temperature, light, solvent quality) shows particular promise for various biomedical applications including drug delivery, tissue engineering, medical diagnostics, and bioseparations. Furthermore, the integration of copolymer architectures into stimuli-responsive materials design enables exquisite control over the locations of responsive sites within self-assembled nanostructures. The combination of new synthesis techniques and well-defined copolymer self-assembly has facilitated substantial developments in stimuli-responsive materials in recent years. In this tutorial review, we discuss several methods that have been employed to synthesize self-assembling and stimuli-responsive copolymers for biomedical applications, and we identify common themes in the response mechanisms among the targeted stimuli. Additionally, we highlight parallels between the chemistries used for generating solution assemblies and those employed for creating copolymer surfaces.

Size evolution of highly amphiphilic macromolecular solution assemblies via a distinct bimodal pathway

The solution self-assembly of macromolecular amphiphiles offers an efficient, bottom-up strategy for producing well--defined nanocarriers, with applications ranging from drug delivery to nanoreactors. Typically, the generation of uniform nanocarrier architecturesis controlled by processing methods that rely upon cosolvent mixtures. These preparation strategies hinge on the assumption that macromolecular solution nanostructures are kinetically stable following transfer from an organic/aqueous cosolvent into aqueous solution. Herein we demonstrate that unequivocal step-change shifts in micelle populations occur over several weeks following transfer into a highly selective solvent. The unexpected micelle growth evolves through a distinct bimodal distribution separated by multiple fusion events and critically depends on solution agitation. Notably, these results underscore fundamental similarities between assembly processes in amphiphilic polymer, small molecule, and protein systems. Moreover, the non-equilibrium micelle size increase can have a major impact on the assumed stability of solution assemblies, for which performance is dictated by nanocarrier size and structure.

Hollow block copolymer nanoparticles through a spontaneous one-step structural reorganization.

The spontaneous one-step synthesis of hollow nanocages and nanotubes from spherical and cylindrical micelles based on poly(acrylic acid)-b-polylactide (P(AA)-b-P(LA)) block copolymers (BCPs) has been achieved. This structural reorganization, which occurs simply upon drying of the samples, was elucidated by transmission electron microscopy (TEM) and atomic force microscopy (AFM). We show that it was necessary to use stain-free imaging to examine these nanoscale assemblies, as the hollow nature of the particles was obscured by application of a heavy metal stain. Additionally, the internal topology of the P(AA)-b-P(LA) particles could be tuned by manipulating the drying conditions to give solid or compartmentalized structures. Upon resuspension, these reorganized nanoparticles retain their hollow structure and display significantly enhanced loading of a hydrophobic dye compared to the original solid cylinders.

Structural changes in block copolymer micelles induced by cosolvent mixtures.

We investigated the influence of tetrahydrofuran (THF) addition on the structure of poly(1,2-butadiene-b-ethylene oxide) [PB-PEO] micelles in aqueous solution. Our studies showed that while the micelles remained starlike, the micelle core-corona interfacial tension and micelle size decreased upon THF addition. The detailed effects of the reduction in interfacial tension were probed using contrast variations in small angle neutron scattering (SANS) experiments. At low THF contents (high interfacial tensions), the SANS data were fit to a micelle form factor that incorporated a radial density distribution of corona chains to account for the starlike micelle profile. However, at higher THF contents (low interfacial tensions), the presence of free chains in solution affected the scattering at high q and required the implementation of a linear combination of micelle and Gaussian coil form factors. These SANS data fits indicated that the reduction in interfacial tension led to broadening of the core-corona interface, which increased the PB chain solvent accessibility at intermediate THF solvent fractions. We also noted that the micelle cores swelled with increasing THF addition, suggesting that previous assumptions of the micelle core solvent content in cosolvent mixtures may not be accurate. Control over the size, corona thickness, and extent of solvent accessible PB in these micelles can be a powerful tool in the development of targeting delivery vehicles.

Catalytic Y-tailed amphiphilic homopolymers – aqueous nanoreactors for high activity, low loading SCS pincer catalysts

A new amphiphilic homopolymer bearing an SCS pincer palladium complex has been synthesized by reversible addition fragmentation chain transfer polymerization. The amphiphile has been shown to form spherical and worm-like micelles in water by cryogenic transmission electron microscopy and small angle neutron scattering. Segregation of reactive components within the palladium containing core results in increased catalytic activity of the pincer compound compared to small molecule analogues. This allows carbon-carbon bond forming reactions to be performed in water with reduced catalyst loadings and enhanced activity.

Unlocking Chain Exchange in Highly Amphiphilic Block Polymer Micellar Systems: Influence of Agitation

Chain exchange between block polymer micelles in highly selective solvents, such as water, is well-known to be arrested under quiescent conditions, yet this work demonstrates that simple agitation methods can induce rapid chain exchange in these solvents. Aqueous solutions containing either pure poly(butadiene-b-ethylene oxide) or pure poly(butadiene-b-ethylene oxide-d4) micelles were combined and then subjected to agitation by vortex mixing, concentric cylinder Couette flow, or nitrogen gas sparging. Subsequently, the extent of chain exchange between micelles was quantified using small angle neutron scattering. Rapid vortex mixing induced chain exchange within minutes, as evidenced by a monotonic decrease in scattered intensity, whereas Couette flow and sparging did not lead to measurable chain exchange over the examined time scale of hours. The linear kinetics with respect to agitation time suggested a surface-limited exchange process at the air–water interface. These findings demonstrate the strong influence of processing conditions on block polymer solution assemblies.